Under the Federal Food, Drug and Cosmetic Act, a drug is considered adulterated if it is not produced in conformance to Current Good Manufacturing Practices (CGMP""s). CGMP""s are defined in 21 Code of Federal Regulations, Parts 210 and 211. Under these regulations, the manufacturers of pharmaceutical products are required to validate their manufacturing processes. A properly validated process provides a high degree of assurance that the resulting product consistently meets predetermined specifications and quality characteristics. For a solid dosage form or compressed tablet, process validation must demonstrate the uniformity of the final powder blend as well as the drug product. In 1993, as a result of a court ruling in United States v. Barr Laboratories, 812 F. Supp. 458 (D.N.J. 1993), this aspect of validation received increased attention from both the industry and the Food and Drug Administration (FDA).
As a result of this court decision, and FDA""s 1996 proposal to amend CGMP regulations to include routine testing of blend homogeneity, the pharmaceutical industry has been faced with the challenge of collecting samples that are truly representative of the final blend. Attempts to develop effective sampling methodology have been frustrating. Presently used methods continue to produce sampling errors on susceptible blends. Often the relative standard deviation (xe2x80x9cRSDxe2x80x9d) of the blend samples is significantly higher than the RSD of the finished product content uniformity results. Some products also tend to show a high or low assay bias on blend sampling that is not reproduced in the finished product test results. As FDA is requiring unit blend testing on all new NDA and ANDA filings, sampling issues continue to be a significant problem.
Currently there are many different sampling systems used to sample blends. One such system is a powder thief which is designed based on the thieves used to sample grains. The technique for sampling with the grain type thief consists of the sampler or operator inserting the thief tip into the powder bed just beyond the sampling location with the port closed. The port is then opened and the thief is rotated or shaken to cause the sample to enter the chamber. The port is then closed and the sample is withdrawn and transferred to a bottle.
However, because grain, unlike pharmaceutical blends, is fairly homogenous it does not segregate based on the properties for which it is being sampled (e.g. mold contamination). Pharmaceutical blends are generally powders of different size, density, shape and cohesiveness. They may be granulated, which helps to maintain homogeneity, once achieved, by xe2x80x9cgluingxe2x80x9d the various ingredients together in granules. In contrast to granulated samples, in direct blends the various ingredients remain free to flow, remix, and demix according to their individual properties. Direct blends have a tendency to segregate when the powder bed is disturbed. Accordingly, there are several problems associated with using the above design for sampling pharmaceutical direct blends. For example, the entry of the thief into the blend disturbs the bed, causing localized mixing or segregation, depending upon the properties of the blended powders. Another problem arises because only a small portion of the blend is required to flow into the sampling port. The flow is thus selective, based on the physical characteristics of the individual ingredients noted above. Electrostatic forces can also cause very fine powders to adhere to the inside of the sampling port as the sample is removed from the thief.
With state-of-the-art powder thieves, the noses of the thieves precede the sampling ports as they are inserted into the powder bed. This causes additional mixing or segregation. The sampling ports, which open perpendicular to the line of entry into the powder bed, require that the granulation be caused to flow into the opening, assisted by rotation of the thief. This places a burden of reproducibility on operator technique and is frequently the source of sampling phenomena. Additionally, they are designed such that the operator must disassemble the thief and remove the sample port in order to transfer the sample to a bottle.
The present invention overcomes these major sampling issues and allows for samples that are representative of the final blend. One embodiment of the thief of the present invention is shown in FIG. 3. The technique for sampling with the thief of the present invention consists of the sampler or operator inserting the thief tip to the sampling location with the cavity plugged. The plug is retracted and the thief is inserted a short distance further into the sample, packing the blend in the cavity and forming a plug of sample. The thief is withdrawn and the plug of sample is partially ejected to a predetermined point. The end of the plug of sample is sliced off and discarded. The remaining plug comprises the sample.
In the thief of the present invention, the sampling cavity resides at the tip of the thief so that the thief has not previously disturbed the area to be sampled. The material in front of the sampling cavity is forced into the cavity intact and compressed into a plug. Removal of the sample is by quick ejection of the plug intact. The influences of operator technique and differences in ingredient physical characteristics are greatly minimized. In addition, removal of the sample is quick and easy.